title: HB-EGF is a paracrine growth stimulator for early tumor prestages in inflammation-associated hepatocarcinogenesis.
abstract: OBJECTIVE
  We studied the impact of heparin-binding epidermal growth factor-like growth factor (HB-EGF) on inflammation-driven hepatocarcinogenesis.
  
  
  METHODS
  HB-EGF expression was determined by qRT-PCR and immunodetection in hepatocellular adenoma and carcinoma and in mesenchymal (MC) and parenchymal liver cells obtained from different models of inflammation. The functions of HB-EGF in early hepatocarcinogenesis were assessed in co-cultures of unaltered and initiated/premalignant hepatocytes.
  
  
  RESULTS
  In human and rat (pre)malignant liver lesions, HB-EGF levels were comparable to that of the surrounding tissue. In inflamed livers HB-EGF was expressed predominantly in MC and was further increased by pro-inflammatory lipopolysaccharide (LPS) or linoleic acid hydroperoxide (LOOH). In culture, DNA-replication occurred rather in initiated/premalignant than unaltered hepatocytes and was further elevated by LOOH- or LPS-stimulated MC-supernatants. The supernatant effects were abrogated by pre-incubation with HB-EGF-neutralizing antisera. HB-EGF itself induced DNA-replication and mitosis preferentially in the initiated/premalignant cells. When transducing hepatocytes with a dominant-negative ErbB1-construct, HB-EGF-induced DNA-replications were blocked completely in unaltered hepatocytes but incompletely in initiated/premalignant cells, which suggests elevated ErbB-mediated signal transduction in first stages of hepatocarcinogenesis.
  
  
  CONCLUSIONS
  Pro-inflammatory stimuli induce the release of HB-EGF from MC, which stimulates DNA-replication in initiated/premalignant hepatocytes. Similar mechanisms may contribute to carcinogenesis in human inflammatory liver diseases.
authors.affiliation: Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sagmeister
authors.forename: Claudia
authors.initials: C
authors.lastname: Drucker
authors.forename: Annemarie
authors.initials: A
authors.lastname: Losert
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.forename: Anahita
authors.initials: A
authors.lastname: Daryabeigi
authors.forename: Wolfram
authors.initials: W
authors.lastname: Parzefall
authors.forename: Nataliya
authors.initials: N
authors.lastname: Rohr-Udilova
authors.forename: Christoph
authors.initials: C
authors.lastname: Bichler
authors.forename: Bård
authors.initials: B
authors.lastname: Smedsrød
authors.forename: Daniela
authors.initials: D
authors.lastname: Kandioler
authors.forename: Thomas
authors.initials: T
authors.lastname: Grünberger
authors.forename: Fritz
authors.initials: F
authors.lastname: Wrba
authors.forename: Rolf
authors.initials: R
authors.lastname: Schulte-Hermann
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
mesh_terms: D018248:Adenoma, Liver Cell / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002455:Cell Division; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D018773:Genes, erbB-1 / Q000235:genetics; D066257:Heparin-binding EGF-like Growth Factor; D006505:Hepatitis / Q000276:immunology* / Q000473:pathology; D022781:Hepatocytes / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008648:Mesoderm / Q000166:cytology; D008938:Mitosis; D009367:Neoplasm Staging; D019899:Paracrine Communication / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
chemical_list: C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins